Search

We consider a system of reaction–diffusion equations including chemotaxis terms and coming out of the modelling of multiple sclerosis. The global existence of strong solutions to this system in any dimension is proved, and it is also shown that the solution is bounded uniformly in time. Finally, a nonlinear stability result is obtained when the chemotaxis term is not too big. We also perform numerical simulations to show the appearance of Turing patterns when the chemotaxis term is large.

A principal concern of ecological research is to unveil the causes behind observed spatio-temporal distributions of species. A key tactic is to correlate observed locations with environmental features, in the form of resource selection functions or other correlative species distribution models. In reality, however, the distribution of any population both affects and is affected by those surrounding it, creating a complex network of feedbacks causing emergent spatio-temporal features that may not correlate with any particular aspect of the underlying environment. Here, we study the way in which the movements of populations in response to one another can affect the spatio-temporal distributions of ecosystems. We construct a stochastic individual-based modelling (IBM) framework, based on stigmergent interactions (i.e. organisms leave marks which cause others to alter their movements) between and within populations. We show how to gain insight into this IBM via mathematical analysis of a partial differential equation (PDE) system given by a continuum limit. We show how the combination of stochastic simulations of the IBM and mathematical analysis of PDEs can be used to categorise emergent patterns into homogeneous vs. heterogeneous, stationary vs. perpetually-fluctuating, and aggregation vs. segregation. In doing so, we develop techniques for understanding spatial bifurcations in stochastic IBMs, grounded in mathematical analysis. Finally, we demonstrate through a simple example how the interplay between environmental features and between-population stigmergent interactions can give rise to predicted spatial distributions that are quite different to those predicted purely by accounting for environmental covariates.

We investigate a reaction-diffusion-chemotaxis system that describes the immune response during an inflammatory attack. The model is a modification of the system proposed in Penner, Ermentrout, and Swigon [SIAM J. Appl. Dyn. Syst., 11 (2012), pp. 629-660]. We introduce a logistic term in the immune cell dynamics to reproduce the macrophages' activation, allowing us to describe the disease evolution from the early stages to the acute phase. We focus on the appearance of pattern solutions and their stability. We discover steady-state (Turing) and wave instabilities and classify the bifurcations deriving the corresponding amplitude equations. We study stationary radially symmetric solutions and show that they reproduce various inflammatory aggregates observed in the clinical practice. Moreover, the model supports oscillating-in-time spatial patterns, thus giving a theoretical explanation of the periodic appearance of inflammatory eruptions typical of recurrent erythema multiforme. A detailed numerical bifurcation analysis indicates that the inclusion of the logistic growth term is crucial for the occurrence of a sequence of bifurcations leading to spatio-temporal chaos. In the parameter space, there are large regions where the model system displays critical behavior.

In this paper we study radially symmetric solutions for our recently proposed reaction–diffusion–chemotaxis model of Multiple Sclerosis. Through a weakly nonlinear expansion we classify the bifurcation at the onset and derive the amplitude equations ruling the formation of concentric demyelinating patterns which reproduce the concentric layers observed in Balò sclerosis and in the early phase of Multiple Sclerosis. We present numerical simulations which illustrate and fit the analytical results.

We investigate the formation of stationary patterns in the FitzHugh-Nagumo reaction-diffusion system with linear cross-diffusion terms. We focus our analysis on the effects of cross-diffusion on the Turing mechanism. Linear stability analysis indicates that positive values of the inhibitor cross-diffusion enlarge the region in the parameter space where a Turing instability is excited. A sufficiently large cross-diffusion coefficient of the inhibitor removes the requirement imposed by the classical Turing mechanism that the inhibitor must diffuse faster than the activator. In an extended region of the parameter space a new phenomenon occurs, namely the existence of a double bifurcation threshold of the inhibitor/activator diffusivity ratio for the onset of patterning instabilities: for large values of inhibitor/activator diffusivity ratio, classical Turing patterns emerge where the two species are in-phase, while, for small values of the diffusion ratio, the analysis predicts the formation of out-of-phase spatial structures (named cross-Turing patterns). In addition, for increasingly large values of the inhibitor cross-diffusion, the upper and lower bifurcation thresholds merge, so that the instability develops independently on the value of the diffusion ratio, whose magnitude selects Turing or cross-Turing patterns. Finally, the pattern selection problem is addressed through a weakly nonlinear analysis.

BACKGROUND Improvements in the design of the endotracheal tube (ETT) have been achieved in recent years. We evaluated tracheal injury associated with ETTs with novel high-volume low-pressure (HVLP) cuffs and subglottic secretions aspiration (SSA) and the effects on mucociliary clearance (MCC). METHODS Twenty-nine pigs were intubated with ETTs comprising cylindrical or tapered cuffs and made of polyvinylchloride (PVC) or polyurethane. In specific ETTs, SSA was performed every 2 h. Following 76 h of mechanical ventilation, pigs were weaned and extubated. Images of the tracheal wall were recorded before intubation, at extubation, and 24 and 96 h thereafter through a fluorescence bronchoscope. We calculated the red-to-green intensity ratio (R/G), an index of tracheal injury, and the green-plus-blue (G+B) intensity, an index of normalcy, of the most injured tracheal regions. MCC was assessed through fluoroscopic tracking of radiopaque markers. After 96 h from extubation, pigs were killed, and a pathologist scored injury. RESULTS Cylindrical cuffs presented a smaller increase in R/G vs tapered cuffs (P = .011). Additionally, cuffs made of polyurethane produced a minor increase in R/G (P = .012) and less G+B intensity decline (P = .022) vs PVC cuffs. Particularly, a cuff made of polyurethane and with a smaller outer diameter outperformed all cuffs. SSA-related histologic injury ranged from cilia loss to subepithelial inflammation. MCC was 0.9 ± 1.8 and 0.4 ± 0.9 mm/min for polyurethane and PVC cuffs, respectively (P CONCLUSIONS HVLP cuffs and SSA produce tracheal injury, and the recovery is incomplete up to 96 h following extubation. Small, cylindrical-shaped cuffs made of polyurethane cause less injury. MCC decline is reduced with polyurethane cuffs.

In the semirecumbent position, gravity-dependent dissemination of pathogens has been implicated in the pathogenesis of ventilator-associated pneumonia. We compared the preventive effects of a ventilatory strategy, aimed at decreasing pulmonary aspiration and enhancing mucus clearance versus the Trendelenburg position.Prospective randomized animal study.Animal research facility, University of Barcelona, Spain.Twenty-four Large White-Landrace pigs.Pigs were intubated and on mechanical ventilation for 72 hours. Following surgical preparation, pigs were randomized to be positioned: 1) in semirecumbent/prone position, ventilated with a duty cycle (TITTOT) of 0.33 and without positive end-expiratory pressure (control); 2) as in the control group, positive end-expiratory pressure of 5 cm H2O and TITTOT to achieve a mean expiratory-inspiratory flow bias of 10 L/min (treatment); 3) in Trendelenburg/prone position and ventilated as in the control group (Trendelenburg). Following randomization, Pseudomonas aeruginosa was instilled into the oropharynx.Mucus clearance rate was measured through fluoroscopic tracking of tracheal markers. Microspheres were instilled into the subglottic trachea to assess pulmonary aspiration. Ventilator-associated pneumonia was confirmed by histological/microbiological studies. The mean expiratory-inspiratory flow in the treatment, control, and Trendelenburg groups were 10.7 ± 1.7, 1.8 ± 3.7 and 4.3 ± 2.8 L/min, respectively (p0.001). Mucus clearance rate was 11.3 ± 9.9 mm/min in the Trendelenburg group versus 0.1 ± 1.0 in the control and 0.2 ± 1.0 in the treatment groups (p = 0.002). In the control group, we recovered 1.35% ± 1.24% of the instilled microspheres per gram of tracheal secretions, whereas 0.22% ± 0.25% and 0.97% ± 1.44% were recovered in the treatment and Trendelenburg groups, respectively (p = 0.031). Ventilator-associated pneumonia developed in 66.67%, 85.71%, and 0% of the animals in the control, treatment, and Trendelenburg groups (p0.001).The Trendelenburg position predominates over expiratory flow bias and positive end-expiratory pressure in the prevention of gravity-dependent translocation of oropharyngeal pathogens and development of ventilator-associated pneumonia. These findings further substantiate the primary role of gravity in the pathogenesis of ventilator-associated pneumonia.

To validate a set of predictors of adverse outcomes in patients with ICU-acquired pneumonia in relation to clinically relevant assessment at 28 days.Prospective, observational study.Six medical and surgical ICUs of a university hospital.Three hundred thirty-five patients with ICU-acquired pneumonia.None.Development of predictors of adverse outcomes was defined when at least one of the following criteria was present at an evaluation made 72-96 hours after starting treatment: no improvement of PaO2/FIO2, need for intubation due to pneumonia, persistence of fever or hypothermia with purulent respiratory secretions, greater than or equal to 50% increase in radiographic infiltrates, or occurrence of septic shock or multiple organ dysfunction syndrome. We also assessed the inflammatory response by different serum biomarkers. The presence of predictors of adverse outcomes was related to mortality and ventilator-free days at day 28. Sequential Organ Failure Assessment score was evaluated and related to mortality at day 28.One hundred eighty-four (55%) patients had at least one predictor of adverse outcomes. The 28-day mortality was higher for those with versus those without predictors of adverse outcomes (45% vs 19%, p0.001), and ventilator-free days were lower (median [interquartile range], 0 [0-17] vs 22 [0-28]) for patients with versus patients without predictors of adverse outcomes (p0.001). The lack of improvement of PaO2/FIO2 and lack of improvement in Sequential Organ Failure Assessment score from day 1 to day 5 were independently associated with 28-day mortality and fewer ventilator-free days. The marginal structural analysis showed an odds ratio of death 2.042 (95% CI, 1.01-4.13; p=0.047) in patients with predictors of adverse outcomes. Patients with predictors of adverse outcomes had higher serum inflammatory response accordingly to biomarkers evaluated.The presence of any predictors of adverse outcomes was associated with mortality and decreased ventilator-free days at day 28. The lack of improvement in the PaO2/FIO2 and Sequential Organ Failure Assessment score was independently associated with mortality in the multivariate analysis.

Tumor derived exosomes are vesicles which contain proteins and microRNAs that mediate cell-cell communication and are involved in angiogenesis and tumor progression. Curcumin derived from the plant Curcuma longa, shows anticancer effects. Exosomes released by CML cells treated with Curcumin contain a high amount of miR-21 that is shuttled into the endothelial cells in a biologically active form. The treatment of HUVECs with CML Curcu-exosomes reduced RhoB expression and negatively modulated endothelial cells motility. We showed that the addition of CML control exosomes to HUVECs caused an increase in IL8 and VCAM1 levels, but Curcu-exosomes reversed these effects thus attenuating their angiogenic properties. This antiangiogenic effect was confirmed with in in vitro and in vivo vascular network formation assays. SWATH analysis of the proteomic profile of Curcu-exosomes revealed that Curcumin treatment deeply changes their molecular properties, in particular, Curcumin induces a release of exosomes depleted in pro-angiogenic proteins and enriched in proteins endowed with anti-angiogenic activity. Among the proteins differential expressed we focused on MARCKS, since it was the most modulated protein and a target of miR-21. Taken together our data indicated that also Curcumin attenuates the exosome's ability to promote the angiogenic phenotype and to modulate the endothelial barrier organization.

Background In this retrospective Italian study, which involved all major national interstitial lung diseases centers, we evaluated the effect of pirfenidone on disease progression in patients with IPF. Methods We retrospectively studied 128 patients diagnosed with mild, moderate or severe IPF, and the decline in lung function monitored during the one-year treatment with pirfenidone was compared with the decline measured during the one-year pre-treatment period. Results At baseline (first pirfenidone prescription), the mean percentage forced vital capacity (FVC) was 75% (35-143%) of predicted, and the mean percentage diffuse lung capacity (DLCO) was 47% (17-120%) of predicted. Forty-eight patients (37.5%) had mild disease (GAP index stage I), 64 patients (50%) had moderate IPF (stage II), and 8 patients (6.3%) had severe disease (stage III). In the whole population, pirfenidone attenuated the decline in FVC (p = 0.065), but did not influence the decline in DLCO (p = 0.355) in comparison to the pre-treatment period. Stratification of patients into mild and severe disease groups based on %FVC level at baseline (>75% and ≤75%) revealed that attenuation of decline in FVC (p = 0.002) was more pronounced in second group of patients. Stratification of patients according to GAP index at baseline (stage I vs. II/III) also revealed that attenuation of decline in lung function was more pronounced in patients with more severe disease. Conclusions In this national experience, pirfenidone reduced the rate of annual FVC decline (p = 0.065). Since pirfenidone provided significant treatment benefit for patients with moderate-severe disease, our results suggest that the drug may also be effective in patients with more advanced disease. Background In this retrospective Italian study, which involved all major national interstitial lung diseases centers, we evaluated the effect of pirfenidone on disease progression in patients with IPF. Methods We retrospectively studied 128 patients diagnosed with mild, moderate or severe IPF, and the decline in lung function monitored during the one-year treatment with pirfenidone was compared with the decline measured during the one-year pre-treatment period. Results At baseline (first pirfenidone prescription), the mean percentage forced vital capacity (FVC) was 75% (35-143%) of predicted, and the mean percentage diffuse lung capacity (DLCO) was 47% (17-120%) of predicted. Forty-eight patients (37.5%) had mild disease (GAP index stage I), 64 patients (50%) had moderate IPF (stage II), and 8 patients (6.3%) had severe disease (stage III). In the whole population, pirfenidone attenuated the decline in FVC (p = 0.065), but did not influence the decline in DLCO (p = 0.355) in comparison to the pre-treatment period. Stratification of patients into mild and severe disease groups based on %FVC level at baseline (>75% and ≤75%) revealed that attenuation of decline in FVC (p = 0.002) was more pronounced in second group of patients. Stratification of patients according to GAP index at baseline (stage I vs. II/III) also revealed that attenuation of decline in lung function was more pronounced in patients with more severe disease. Conclusions In this national experience, pirfenidone reduced the rate of annual FVC decline (p = 0.065). Since pirfenidone provided significant treatment benefit for patients with moderate-severe disease, our results suggest that the drug may also be effective in patients with more advanced disease.

Background: Animal models of ventilator-associated pneumonia (VAP) in primates, sheep, and pigs differ in the underlying pulmonary injury, etiology, bacterial inoculation methods, and time to onset. The most common ovine and porcine models do not reproduce the primary pathogenic mechanism of the disease, through the aspiration of oropharyngeal pathogens, or the most prevalent human etiology. Herein the authors characterize a novel porcine model of VAP due to aspiration of oropharyngeal secretions colonized by Pseudomonas aeruginosa. Methods: Ten healthy pigs were intubated, positioned in anti-Trendelenburg, and mechanically ventilated for 72 h. Three animals did not receive bacterial challenge, whereas in seven animals, a P. aeruginosa suspension was instilled into the oropharynx. Tracheal aspirates were cultured and respiratory mechanics were recorded. On autopsy, lobar samples were obtained to corroborate VAP through microbiological and histological studies. Results: In animals not challenged, diverse bacterial colonization of the airways was found and monolobar VAP rarely developed. In animals with P. aeruginosa challenge, colonization of tracheal secretion increased up to 6.39 ± 0.34 log colony-forming unit (cfu)/ml (P < 0.001). VAP was confirmed in six of seven pigs, in 78% of the cases developed in the dependent lung segments (right medium and lower lobes, P = 0.032). The static respiratory system elastance worsened to 41.5 ± 5.8 cm H2O/l (P = 0.001). Conclusions: The authors devised a VAP model caused by aspiration of oropharyngeal P. aeruginosa, a frequent causative pathogen of human VAP. The model also overcomes the practical and legislative limitations associated with the use of primates. The authors’ model could be employed to study pathophysiologic mechanisms, as well as novel diagnostic/preventive strategies.

The use of corticosteroids is frequent in critically-ill patients. However, little information is available on their effects in patients with intensive care unit-acquired pneumonia. We assessed patients' characteristics, microbial etiology, inflammatory response, and outcomes of previous corticosteroid use in patients with intensive care unit-acquired pneumonia.Prospective observational study.Intensive care units of a university teaching hospital.Three hundred sixteen patients with intensive care unit-acquired pneumonia. Patients were divided according to previous systemic steroid use at onset of pneumonia.None.Survival at 28 days was analyzed using Cox regression, with adjustment for the propensity for receiving steroid therapy. One hundred twenty-five (40%) patients were receiving steroids at onset of pneumonia. Despite similar baseline clinical severity, steroid treatment was associated with decreased 28-day survival (adjusted hazard ratio for propensity score and mortality predictors 2.503; 95% confidence interval 1.176-5.330; p = .017) and decreased systemic inflammatory response. In post hoc analyses, steroid treatment had an impact on survival in patients with nonventilator intensive care unit-acquired pneumonia, those with lower baseline severity and organ dysfunction, and those without etiologic diagnosis or bacteremia. The cumulative dosage of corticosteroids had no significant effect on the risk of death, but bacterial burden upon diagnosis was higher in patients receiving steroid therapy.In critically-ill patients, systemic corticosteroids should be used very cautiously because this treatment is strongly associated with increased risk of death in patients with intensive care unit-acquired pneumonia, particularly in the absence of established indications and in patients with lower baseline severity. Decreased inflammatory response may result in delayed clinical suspicion of intensive care unit-acquired pneumonia and higher bacterial count.

Ultrasound interstitial syndrome is an echographic pattern of the lung characterized by the presence of multiple acoustic artifacts called "comets" or B-lines. It correlates to increase in extravascular lung water and to interstitial lung disease. From the physical and genetic point of view, the characteristics and the entity of this correlation have not yet been studied. The purpose of this study was to extrapolate past observations and demonstrate how comets or B-lines are artifactual images whose formation is linked to ultrasound interactions on discretely aerated tissues of variable density. Echographic comets were studied by scanning a wet synthetic, partially aerated polyurethane sponge (phantom). Density of the phantom in different drying phases was measured and correlated to the presence of echographic artifacts. Artifacts (comets) showed a different concentration from a completely white artifactual field to presence of rare comets. Their density correlates with porosity and geometry of the phantom. In our opinion, comets represent superficial, artifactual, density and geometry correlated phenomenon due to the acoustic permeability of a broken (collapsed) specular reflector, normally present when the phantom is dry.

Background and aims: Bronchiectasis is defined as an abnormal and irreversible dilatation of the bronchi, often associated with chronic productive cough, airway obstruction, and recurrent infections. Methods: MEDLINE data from 1978 to November 2008 was analysed. Search was limited to randomized control trials, clinical trials, meta-analysis, reviews published in English, using the keyword bronchiectasis. Results: The prevalence of bronchiectasis is unknown. However, prevalence seems to increase with age from 4.2 per 100 000 persons aged 18–34 years to 271.8 per 100 000 among those aged 75 years or older. Therapy is aimed to limit the cycle of infection and inflammation and to reduce the number of exacerbations, in order to improve quality of life. Conclusions: Bronchiectasis still remain a significant health problem. Further research is required to improve the management of this herterogeneous condition. Please cite this paper as: Pappalettera M, Aliberti S, Castellotti P, Ruvolo L, Giunta V and Blasi F. Bronchiectasis: an update. The Clinical Respiratory Journal 2009; 3: 126–134.

In immunocompetent patients with nosocomial pneumonia, the relationship between Candida spp. isolation in respiratory samples and outcomes or association with other pathogens is controversial. We therefore compared the characteristics and outcomes of patients with intensive care unit-acquired pneumonia (ICUAP), with or without Candida spp. isolation in the respiratory tract. In this prospective non-interventional study, we assessed 385 consecutive immunocompetent patients with ICUAP, according to the presence or absence of Candida spp. in lower respiratory tract samples. Candida spp. was isolated in at least one sample in 82 (21%) patients. Patients with Candida spp. had higher severity scores and organ dysfunction at admission and at onset of pneumonia. In multivariate analysis, previous surgery, diabetes mellitus and higher Simplified Acute Physiology Score II at ICU admission independently predicted isolation of Candida spp. There were no significant differences in the rate of specific aetiological pathogens, the systemic inflammatory response, and length of stay between patients with and without Candida spp. Mortality was also similar, even adjusted for potential confounders in propensity-adjusted multivariate analyses (adjusted hazard ratio 1.08, 95% CI 0.57-2.05, p 0.80 for 28-day mortality and adjusted hazard ratio 1.38, 95% CI 0.81-2.35, p 0.24 for 90-day mortality). Antifungal therapy was more frequently prescribed in patients with Candida spp. in respiratory samples but did not influence outcomes. Candida spp. airway isolation in patients with ICUAP is associated with more initial disease severity but does not influence outcomes in these patients, regardless of the use or not of antifungal therapy.

Metabolic syndrome (MS), formerly known as X-syndrome, is a clinical and laboratory entity involving obesity, hypertension, and borderline fasting glucose, high triglyceride and low HDL cholesterol levels, that is considered to be a counterpart of insulin resistance with overweight playing a key role; increased insulin, leptin, adiponectin and resistin levels link its various features and some common flanking findings such as hypercholesterolemia, hyperuricemia and hyperferritinemia. Clinical and laboratory data reminiscent of metabolic syndrome are commonly observed after hematopoietic stem cell transplantation (HSCT). We evaluated the body mass index (BMI), routine lipid and glucidic markers, and common endocrinologic parameters in 37 HSCT recipients (19 males; median age 45 years, range 26–60; 22 autologous, 15 allogeneic) whose continuous CR lasted at least five years; insulin (baseline and after an oral glucose test), leptin, resistin, TNF-alpha and adiponectin levels were also detemined. Diabetic HSCT recipients were excluded. The control group consisted of 23 healthy volunteers of comparable age and sex without a family history of diabetes. In comparison with the controls, the HSCT recipients had significantly increased levels of TNF (median 10.05 vs 9.3 pg/mL, p=0.034), insulin (13.6 vs 10.1 mIU/mL, p=0.029) and leptin (13.71 vs 3.69 ng/mL, p= 0.02); there were no significant differences in adiponectin and resistin levels, BMI or the other considered parameters. In comparison with the other HSCT recipients, the 16 patients with higher baseline insulin levels (>15 mIU/mL) had significantly higher leptin levels (median 23.665 vs 8.3, p

Introduction Laboratory studies demonstrated that the lateral Trendelenburg position (LTP) is superior to the semirecumbent position (SRP) in the prevention of ventilator-associated pulmonary infections. We assessed whether the LTP could also prevent pulmonary colonization and infections caused by an endotracheal tube (ETT) biofilm. Methods Eighteen pigs were intubated with ETTs colonized by Pseudomonas aeruginosa biofilm. Pigs were positioned in LTP and randomized to be on mechanical ventilatin (MV) up to 24 hour, 48 hour, 48 hour with acute lung injury (ALI) by oleic acid and 72 hour. Bacteriologic and microscopy studies confirmed presence of biofilm within the ETT. Upon autopsy, samples from the proximal and distal airways were excised for P.aeruginosa quantification. Ventilator-associated tracheobronchitis (VAT) was confirmed by bronchial tissue culture ≥3 log colony forming units per gram (cfu/g). In pulmonary lobes with gross findings of pneumonia, ventilator-associated pneumonia (VAP) was confirmed by lung tissue culture ≥3 log cfu/g. Results P.aeruginosa colonized the internal lumen of 16 out of 18 ETTs (88.89%), and a mature biofilm was consistently present. P.aeruginosa colonization did not differ among groups, and was found in 23.6% of samples from the proximal airways, and in 7.1% from the distal bronchi (P = 0.001). Animals of the 24 hour group never developed respiratory infections, whereas 20%, 60% and 25% of the animals in group 48 hour, 48 hour-ALI and 72 hour developed P.aeruginosa VAT, respectively (P = 0.327). Nevertheless, VAP never developed. Conclusions Our findings imply that during the course of invasive MV up to 72 hour, an ETT P.aeruginosa biofilm hastily colonizes the respiratory tract. Yet, the LTP compartmentalizes colonization and infection within the proximal airways and VAP never develops.